2. Academic Validation
  3. USP7 limits CDK1 activity throughout the cell cycle

USP7 limits CDK1 activity throughout the cell cycle

  • EMBO J. 2021 Jun 1;40(11):e99692. doi: 10.15252/embj.201899692.
Antonio Galarreta 1,  Pablo Valledor 1,  Patricia Ubieto-Capella 1,  Vanesa Lafarga 1,  Eduardo Zarzuela 2,  Javier Muñoz 2,  Marcos Malumbres 3,  Emilio Lecona 4,  Oscar Fernandez-Capetillo 1 5
Affiliations

Affiliations

  • 1 Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 2 Proteomics Unit, Spanish National Cancer Research Centre (CNIO) and ProteoRed-ISCIII, Madrid, Spain.
  • 3 Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 4 Chromatin, Cancer and the Ubiquitin System lab, Centre for Molecular Biology Severo Ochoa (CBMSO), Madrid, Spain.
  • 5 Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
PMID: 33856059 DOI: 10.15252/embj.201899692
Abstract

Chemical inhibitors of the Deubiquitinase USP7 are currently being developed as Anticancer agents based on their capacity to stabilize P53. Regardless of this activity, USP7 inhibitors also generate DNA damage in a p53-independent manner. However, the mechanism of this genotoxicity and its contribution to the Anticancer effects of USP7 inhibitors are still under debate. Here we show that, surprisingly, even if USP7 inhibitors stop DNA replication, they also induce a widespread activation of CDK1 throughout the cell cycle, which leads to DNA damage and is toxic for mammalian cells. In addition, USP7 interacts with the Phosphatase PP2A and supports its active localization in the cytoplasm. Accordingly, inhibition of USP7 or PP2A triggers very similar changes of the phosphoproteome, including a widespread increase in the phosphorylation of CDK1 targets. Importantly, the toxicity of USP7 inhibitors is alleviated by lowering CDK1 activity or by chemical activation of PP2A. Our work reveals that USP7 limits CDK1 activity at all cell cycle stages, providing a novel mechanism that explains the toxicity of USP7 inhibitors through untimely activation of CDK1.

Keywords

CDK1; USP7; anticancer drugs; cell cycle; deubiquitinase.

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